Bicyclic heterocycles for the treatment of diabetes and other diseases

1. A compound having the structure

wherein:

a) p is 0, 1 or 2;

b) L, M, N, Q and T residues are independently selected from, —O—, —S(O)—, —S(O)—, —S(O) 2 −, —N(R 203 )—, —N(R 204 )—, —C(R 205 )(R 206 )—, —C(R 207 ) (R 208 )—, or —C(R 209 )(R 210 )— radicals, with the proviso that one or two of the L, M, N, Q or T radicals can be absent;

c) R 200 , R 201 , R 202 , R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , and R 210 are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;

d) Ar10 is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl radical comprising 2 to 18 carbon atoms;

e) the radical

comprises from 6 to 20 carbon atoms;

f) R 211 is hydrogen, hydroxy, or an organic residue comprising 1 to 10 carbon atoms;

g) - - - is either present or absent; and

h) HAr has the structure

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein p is 0.

3. The compound of claim 1 wherein the radical

has the structure

4. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 8 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide;

R 201 and R 202 are independently selected from hydrogen or a halogen; and

R 203 , R 207 and R 208 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

5. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 10 carbon atoms and is selected from an ailcyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide.

6. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 4 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkyithiocarbamate, aryl, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide; and R 207 and R 208 are independently selected from hydrogen or an alkyl comprising 1 to 10 carbon atoms.

7. The compound of claim 4 wherein the R 207 and R 208 , residues are connected together to form an exocyclic substituent residue comprising 3 to 6 ring carbon atoms and from 1 to 3 optional ring heteroatoms selected from O, S, or N.

8. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 10 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide; and

R 201 and R 202 are independently selected from hydrogen or a halogen; and

R 205 , R 206 , R 207 , and R 208 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

9. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 10 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide; and

R 205 , R 206 , R 207 , R 208 R 209 , and R 210 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

10. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 10 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkyithiocarbamate, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide; and

R 203 , R 204 , R 205 , R 206 , R 207 , and R 208 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

11. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 10 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide; and

R 205 and R 206 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

12. The compound of claim 1 wherein p is 1 or 2.

13. The compound of claim 1 wherein the radical

has the structure

wherein R 200 comprises 1 to 10 carbon atoms and is selected from the group consisting of an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide,

R 201 is hydrogen or a halide; and

R 205 , R 206 , R 207 , and R 208 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

14. The compound of claim 1 wherein R 200 comprises to 8 carbon atoms and is selected from an alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide.

15. The compound of claim 1 wherein R 200 is an aryl, substituted aryl, heteroaryl, or substituted aryl having the structure

wherein R 222 , R 223 and R 223 are independently selected from hydrogen, an alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, alkyithiocarbamate, substituted alkyithiocarbamate, aryithiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

and r is 1, 2 or 3.

16. The compound of claim 1 wherein R 200 is a heteroaryl, or substituted aryl having the structure

wherein R 222 , R 223 and R 224 are independently selected from hydrogen, an alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, alkyithiocarbamate, substituted alkyithiocarbamate, aryithiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide.

17. The compound of claim 1 wherein R 200 is a heteroaryl, or substituted aryl having the structure

wherein R 222 , R 223 and R 224 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms.

18. The compound of claim 1 wherein R 200 has the structure

19. The compound of claim 1 wherein Ar 10 comprises from 3 to 6 ring carbon atoms and optionally 1 to 3 ring heteroatoms selected from O, S, or N.

20. The compound of claim 1 wherein Ar 10 comprises a benzene or pyridine ring.

21. The compound of claim 1 wherein Ar 10 has the structure

wherein R 230 , R 231 , R 232 and R 233 are independently selected from hydrogen, alkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, substituted alkylthiocarbamate, arylthiocarbamate, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide.

22. The compound of claim 21 wherein R 230 is not hydrogen.

23. The compound of claim 1 wherein Ar 10 has the structure

wherein R 231 , R 232 and R 233 are independently selected from hydrogen or a halogen.

24. The compound of claim 1 wherein R 211 is hydrogen or an alkyl having from 1 to 4 carbon atoms.

25. The compound of claim 1 wherein R 211 is hydrogen.

26. The compound of claim 1 wherein - - - is present.

27. The compound of claim 1 wherein HAr has the structure

28. The compound of claim 27 wherein - - - is present.

29. The compound of claim 27 wherein - - - is absent.

30. The compound of claim 1 wherein HAr has the structure

31. The compound of claim 4 wherein HAr has the structure

32. The compound of claim 31 wherein Ar 10 has the structure

wherein R 230 , R 231 , R 232 and R 233 are independently selected from hydrogen, halogen, hydroxyl, amino, or a radical comprising 1 to 4 carbon atoms selected from alkyl, haloalkyl, acyloxy, mono-substituted amino, di-substituted amino, acyl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide; with the proviso that R 230 is not hydrogen.

33. The compound of claim 32 wherein R 211 is hydrogen and wherein - - - is present.

34. A compound of claim 1 that is effective, when applied at a concentration of about 1 μM for a period of about 7 days, to induce differentiation of mouse preadipocyte 3T3-L1 cells.

35. A compound of claim 1 that is effective, when orally administered to KKA y mice at a concentration of about 15 mg/kg for a period of about 7 days to decrease the serum glucose levels of the KKA y mice by at least about 10%.

36. A compound of claim 1 that is effective, when orally administered to KKA y mice at a concentration of about 15 mg/kg for a period of about 7 days to decrease the serum triglyceride levels of the KKA y mice by at least about 10%.

37. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, and one or more compounds of claim 1 in an amount effective for treating diabetes or obesity, or modulating lipid metabolism, carbohydrate metabolism, lipid and carbohydrate metabolism in a mammal.

38. A method of making the compound of claim 1 comprising

a) coupling

i) a bicyclic heterocycle precursor compound having the structure

ii) with an Ar 10 precursor compound having the structure

iii) to form a carbonyl containing precursor compound having the formula

b) further reacting the carbonyl containing precursor compound so as to connect to the carbonyl of the carbonyl containing precursor the HAr heterocycle.

39. The method of claim 38 wherein the further reacting comprises condensing the carbonyl containing precursor compound with a compound having the formula

40. A compound having the structure

wherein:

a) the bicyclic radical

has the structure

wherein R 200 comprises 1 to 8 carbon atoms and is selected from the group consisting of an alkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide;

R 201 and R 202 are independently selected from hydrogen or a halogen; and

R 203 , R 207 and R 208 are independently selected from hydrogen or an alkyl comprising 1 to 4 carbon atoms;

b) W, X, Y and Z form a heterocycle having the structure

c) - - - is either present or absent;

d) Ar 10 has the structure

wherein R 230 , R 231 , R 232 and R 233 are independently selected from hydrogen, alkyl, haloalkyl, halogen, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, acyl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide, with the proviso that R 230 is not hydrogen; and

e) R 211 is hydrogen or an alkyl having from 1 to 4 carbon atoms;

or a pharmaceutically acceptable salt thereof.

41. A compound having the structure

wherein:

a) R 200 comprises 1 to 4 carbon atoms and is selected from the group consisting of an alkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-alkyl-amino, dialkyl-amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, aryl, heteroaryl, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide;

b) W, X, Y and Z form a heterocycle having the structure

c) Ar 10 has the structure

wherein R 231 , R 232 and R 233 are independently selected from hydrogen or a halogen.

42. A compound of Formula (300):

wherein:

a) R 200 , R 201 and R 202 are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic residue comprising 1 to 12 carbon atoms;

b) N p are the number of heteroaryl ring nitrogens selected from 0, 1 or 2;

c) L, M, N, Q and T residues are independently selected from —C(O)—, —C(S)—, —O—, —S—, —N(R 203 )—, —N(R 204 )—, —C(R 205 )(R 206 )—, —C(R 207 )(R 208 )—, or —C(R 209 )(R 210 )— residues, and from zero to two of the L, M, N, Q or T residues can be absent;

wherein

i) R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , and R 210 are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic residue comprising 1 to 12 carbon atoms; or two of the R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 and R 210 residues can be connected together to form an exocyclic substituent residue comprising 1 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selected from O, S, or N; and

(ii) L, M, N, Q and T do not form an amide residue;

d) Ar 10 is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl residue comprising from 3 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selected from O, S, or N;

e) R 211 is hydrogen, hydroxy, or an organic residue comprising 1 to 10 carbon atoms;

f) - - - is either present or absent;

g) W, X, Y and Z form a 2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue;

 2,4-imidazolidinedione 2-thioxo-imidazolidine-4-one

or a pharmaceutically acceptable salt thereof.

43. A compound having the formula:

5-[3-(5-Isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione;

5-[2,5-Difluoro-3-(5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-methoxy-benzylidene]-thiazolidine-2,4-dione; or

5-[3-(5-Furan-3-yl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof.

44. A compound having the formula:

5-[3-(5-Isobutyryl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

7-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-trlfluoromethoy-phenyl]-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid methylamide,

7-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-trifluoromethoxy-phenyl]-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid dimethylamide,

5-[3-(3,3-Dimethyl-5-propionyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

5-[4-Dimethylamino-3-(5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofiiran-7-yl)-benzylidene]-thiazolidine-2,4-dione,

7-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-trifluoromethoxy-phenyl]-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid methyl ester,

2-[3,3-Dimethyl-7-(2-trifluoromethoxy-5-vinyl-phenyl)-2,3-dihydro-benzofuran-5-ylmethoxy]-ethanol,

5-[3-(5-Methoxymethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

7-[5-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-trifluoromethoxy-phenyl]-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid,

5-[3-(5-Dimethylaminomethyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

7-[5-(2,4Dioxo-thiazolidin-5-ylidenemethyl)-2-trifluoromethoxy-phenyl]-3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide,

5-[3-(5-Methanesulfonyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

5-[3-(5-Acetyl-3,3-dimethyl-2,3-dihydro-benzofurafl-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

5-[3-(5-Isoxazol-5-yl-3,3-dimethyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione,

5-[3-(6-isobutyl-benzo[1,3]dioxol-4-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, or

5-[3-(3,3-Dimethyl-5-oxazol-2-yl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione;

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 42 wherein p is 0.

46. The compound of claim 45 wherein R 200 is a C 1 –C 8 straight or branched alkyl and R 201 and R 202 are hydrogen.

47. The compound of claim 46 wherein R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , and R 210 are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic residue comprising 1 to 4 carbon atoms.

48. The compound of claim 42 wherein the radical

has the structure

49. The compound of claim 48 wherein R 200 is a C1–C8 straight or branched alkyl and R 201 and R 202 are hydrogen; and R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , and R 210 are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 4 carbon atoms.

50. The compound of claim 42 wherein the radical

has the structure

wherein:

R 200 is hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, ailcyithiocarbamate, substituted alkylthiocarbamate, arylthiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

R 201 and R 202 are hydrogen or halogen; and

R 207 and R 208 are an alkyl or substituted alkyl comprising from 1 to 4 carbon atoms.

51. The compound of claim 42 wherein the radical

has the structure

wherein:

R 200 is hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, alkyithiocarbamate, substituted alkyithiocarbamate, aryithiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloallcyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

R 201 and R 202 are hydrogen or halogen; and

R 203 , R 207 , and R 208 are an alkyl or substituted alkyl comprising from 1 to 4 carbon atoms.

52. The compound of claim 42 wherein the radical

has the structure

wherein R 200 is an organic radical comprising 1 to 8 carbon atoms selected from an alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, substituted alkylthiocarbamate, arylthiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide radical; and R 201 and R 202 are hydrogen; and R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , and R 210 are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 4 carbon atoms.

53. The compound of claim 42 wherein the radical

has the structure

wherein:

R 200 is hydrogen, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, substituted alkylthiocarbamate, arylthiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;

R 201 and R 202 are hydrogen or halogen; and

R 207 and R 208 are an alkyl or substituted alkyl comprising from 1 to 4 carbon atoms.

54. The compound of claim 42 wherein Ar 10 has the structure

wherein R 230 , R 231 , R 232 and R 233 are independently selected from hydrogen, alkyl, haloalkyl, halogen, cyano, nitro, hydroxyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, substituted alkylthiocarbamate, arylthiocarbamate, alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide.

55. The compound of claim 54 wherein R 230 is not hydrogen.

56. The compound of claim 42 wherein Ar 10 has the structure

wherein R 231 , R 232 and R 233 are independently selected from hydrogen or a halogen.

57. The compound of claim 53 wherein Ar 10 has the structure

wherein R 231 , R 232 and R 233 are independently selected from hydrogen or a halogen.

58. The compound of claim 57 wherein R 211 is hydrogen.

59. The compound of claim 58 wherein - - - is present.

60. The compound of claim 59 wherein the heterocycle comprising W, X, Y and Z has the structure

61. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, and one or more compounds of claim 42 in an amount effective for treating diabetes, or modulating lipid metabolism or carbohydrate metabolism in a mammal.